Drug Development and Medicinal Chemistry Efforts toward SARS‐Coronavirus and Covid‐19 Therapeutics

Abstract

The COVID‐19 pandemic caused by SARS‐CoV‐2 infection is spreading at an alarming rate and has created an unprecedented health emergency around the globe. There is no effective vaccine or approved drug treatment against COVID‐19 and other pathogenic coronaviruses. The development of antiviral agents is an urgent priority. Biochemical events critical to the coronavirus replication cycle provided a number of attractive targets for drug development. These include, spike protein for binding to host cell‐surface receptors, proteolytic enzymes that are essential for processing polyproteins into mature viruses, and RNA‐dependent RNA polymerase for RNA replication. There has been a lot of ground work for drug discovery and development against these targets. Also, high‐throughput screening efforts have led to the identification of diverse lead structures, including natural product‐derived molecules. This review highlights past and present drug discovery and medicinal‐chemistry approaches against SARS‐CoV, MERS‐CoV and COVID‐19 targets. The review hopes to stimulate further research and will be a useful guide to the development of effective therapies against COVID‐19 and other pathogenic coronaviruses.

Mechanism and inhibition of the papain‐like protease, PLpro, of SARS‐CoV‐2

“…SARS PLpro has been the focus of academic drug discovery efforts in the last two decades (Ghosh et al , ). An initial series of non‐covalent small molecules (Ratia et al , ) was subsequently refined to achieve sub‐μM inhibitors of SARS PLpro with high specificity and low cytotoxicity (Baez‐Santos et al , , ).…”

“…As a result, coronaviruses with blocked protease activity lose their ability to replicate in cells (Kim et al , ). Drugging the proteases in SARS‐CoV‐2 is therefore a current focus of concerted global academic and pharma efforts (Ghosh et al , ).…”

Broad-spectrum inhibition of coronavirus main and papain-like proteases by HCV drugs

“…In SARS-CoV-2 and other coronaviruses this processing is achieved by the papain-like protease (PLpro) and 3C-like or main protease (3CLpro/Mpro). These two enzymes are each cysteine proteases essential for coronavirus replication and therefore are attractive drug targets; each has been successfully targeted previously by antiviral inhibitors (reviewed in (9)).…”

“…In this study, we targeted both proteases (PLpro and 3CLpro) from SARS-CoV-2 by first screening each enzyme against a library of FDA approved antiviral drugs or molecules in pharmaceutical development. We utilized well-established enzymatic assays for each protease (9)(10)(11) and first screened each enzyme for inhibition by drugs that are used to treat Hepatitis C virus (HCV) infections ( Fig. 1).…”

Hijacking SARS-Cov-2/ACE2 receptor interaction by natural and semi-synthetic steroidal agents acting on functional pockets on receptor binding region

“…One of such approaches is to prevent the S protein/ACE2 interaction as a strategy to prevent SARS-CoV-2 entry into target cells. Indeed, and virtual screening campaigns have already identified small molecules able to bind residues at the interface between the RBD of SARS-CoV-2 S protein and the ACE2 receptor (Ghosh et al, 2020;Micholas and Jeremy C., 2020;Senathilake et al, 2020;Utomo et al, 2020;Yan et al, 2020b;Zhou et al, 2020).…”